1. Field of the Invention
The invention is concerned with the production of endogenous prostaglandins by mammals and more specifically concerns a method of raising prostaglandin production levels in the mammal by administering 1-pyridylalkyl-3-phenylureas. The invention also concerns a novel group of substituted 1-pyridylalkyl-3-phenylureas and therapeutic compositions thereof.
2. Description of the Prior Art
Natural prostaglandins are a well-known group of physiologically active unsaturated hydroxy-substituted fatty acids which are biosynthesized endogenously by mammals such as, for example, canines, bovines, equines, swine, and humans. Identified roles of the natural prostaglandins in mammalian physiology are illustrated by their action as mediators in the inflammatory process, as tonal agents in effecting the contractility of smooth muscle and as activators in a wide variety of mammalian reproductive processes.
Structurally, the natural prostaglandins have been arbitrarily classified into four basic families termed "PGE", "PGF", "PGA", and "PGB", respectively. The various families are composed of differing analogs and stereoisomers having as a hypothetical parent structure, prostanoic acid. For example, the principal members of the PGE family are 11.alpha. ,15-hydroxy-9-keto-prosta-13-enoic acid (referred to alternatively for convenience as "PGE.sub.1 "); 11.alpha.,15-dihydroxy-9-keto-prosta-5,13-dienoic acid (hereinafter referred to alternatively as "PGE.sub.2 "); and 11.alpha.,15-dihydroxy-9-keto-prosta-5,13,17-trienoic acid (referred to alternatively for convenience as "PGE.sub.3 "). The principal members of the PGF family are 9.alpha. ,11.alpha.,15-trihydroxy-prosta 13 enoic acid (referred to alternatively for convenience as "PGF.sub.1 .alpha."); 9.beta.,11.alpha.,15-trihydroxy-prosta-13-enoic acid (referred to alternatively for convenience as "PGF.sub.1 .beta."); 9.alpha.,11.alpha.,15-trihydroxy-prosta-5,13-dienoic acid (hereinafter referred to alternatively for convenience as "PGF.sub.2 .alpha."); 9.beta.,11.alpha.,15-trihydroxy-prosta-5,13-dienoic acid (referred to alternatively as "PGF.sub.2 .beta."); and 9.alpha.,11.alpha.,15-trihydroxy prosta-5,13,17-trienoic acid (referred to alternatively as "PGF.sub.3 .alpha.").
Physiological activity of specific natural prostaglandin compounds may be the same, different in degree or differ from the physiologic activity of other specific natural prostaglandins. It appears, however, that they all share a common property in not being continually produced and released by the mammalian tissues of origin. Instead, the prostaglandins appear to be spontaneously synthesized in situ (biosynthesis being equivalent to release) in response to certain stimuli or "trigger" mechanisms. The prostaglandins generally exhibit an extremely short biological half-life and current knowledge indicates that there is no storage of prostaglandins by body tissues or fluids, with the possible exception of seminal fluids. It has been suggested that the trigger or stimulus for endogenous prostaglandin synthesis is associated with trauma of cellular membranes. Such trauma may occur through physical or chemical activity. For example, in the normal mammal carrying a fetus, circulating blood and amniotic fluids do not contain significant amounts of the prostaglandins PGE.sub.2 and PGF.sub.2 .alpha. until birth is imminent. At that time the levels of PGE.sub.2 and PGF.sub.2 .alpha. produced by placental and uterine tissues rise substantially. The suggested function of the prostaglandins at this stage of pregnancy is to stimulate uterine contractions, i.e., labor induction. As another example, injury to mammalian epidermal tissue triggers the in situ synthesis of PGE.sub.2 at the site of injury. PGE.sub.2 is known to promote and accelerate healing of epidermal wounds (see, for example, U.S. Pat. No. 3,711,515 at Column 5, lines 1-11).
We have discovered that the quantity of prostaglandins produced endogenously by a mammal following the stimulation of biosynthesis will be greatly enhanced, e.g., by from 5 to 10 percent to several times normal production, when certain 1-pyridylalkyl-3-phenylureas have been systemically administered to the mammal prior to the stimulation of biosynthesis by normal trigger mechanisms.
Prior to our invention there was a suggestion that thrombin caused an increase in the production levels of PGE.sub.2 and PGF.sub.2 .alpha. by mammalian blood platelets (Smith et al., Nature New Biol. 231-235).
Prior to our invention the treatment of clinical conditions responsive to the presence of prostaglandins had been limited to the administration of prostaglandins from exogenous sources. The method of our invention has a number of advantages over the administration of exogenous prostaglandins. For example, as mentioned above, the biological half-life of the naturally occurring prostaglandins is extremely short. Illustratively, it has been reported that after about 20 minutes, 500 .mu.g. of PGF.sub.2 .alpha. administered intravenously to an adult human cannot be detected in the body. Therefore, to treat clinical conditions such as an epidermal injury with exogenous sources of prostaglandins, it is necessary to employ a continuous administration of the desired prostaglandin over a prolonged period of time. By our method, therapeutic levels of the desired prostaglandin are delivered at the "target site" or site of injury with maximum efficiency. Sustained high levels of prostaglandin are observed for several hours following treatment according to our method thus eliminating the need for continuous exogenous prostaglandin administration over long periods of time. In addition, the systemic administration of exogenous prostaglandins delivers the prostaglandin to organs and tissues other than those at the desired target site. This may result in undesirable responses or "side effects". By the method of our invention, therapeutic levels of natural prostaglandins are produced at the target site, i.e., at the point of epidermal injury or at the locality stimulating synthesis. This reduces the likelihood of responses in remotely located tissues, minimizing side-effects.
Prior hereto, a number of 1-pyridylalkyl and 1-alkylpyridylalkyl-3-phenylureas were known. See, for example, U.S. Pat. Nos. 3,128,280; 3,700,678; Skinner, et al., J. Org. Chem. 25, 2046, (1960); Scully et al., J. Am. Chem. Soc., 75, 3400, (1973); Robison et al., J. Am. Chem. Soc., 77, 6554, (1955); Shibanov et al., U.S.S.R., 194, 825, (1967); Novikov et al., 2h. Prikl. Khim., 42, 2373 (1969; Juby et al., J. Med. Chem., 10, 491, (1967); and Novikov, Khim. Geterotsikl. Soedin., (1), 115-116, (1968).